The present invention is directed to imidazolyl derivatives which are useful as prenyl transferase inhibitors.
The Ras family of proteins are important in the signal transduction pathway modulating cell growth. The protein is produced in the ribosome, released into the cytosol, and post-translationally modified. The first step in the series of post-translational modifications is the alkylation of Cys168 with farnesyl or geranylgeranyl pyrophosphate in a reaction catalyzed by prenyl transferase enzymes such as farnesyl transferase and geranylgeranyl transferase (Hancock, J F, et al., Cell 57:1167-1177 (1989)). Subsequently, the three C-terminal amino acids are cleaved (Gutierrez, L., et al., EMBO J. 8:1093-1098 (1989)), and the terminal Cys is converted to a methyl ester (Clark, S., et al., Proc. Nat""l Acad. Sci. (USA) 85:4643-647 (1988)). Some forms of Ras are also reversibly palmitoylated on cysteine residues immediately N-terminal to Cys168 (Buss, J E et al., Mol. Cell. Biol. 6:116-122 (1986)). It is believed that these modifications increase the hydrophobicity of the C-terminal region of Ras, causing it to localize at the surface of the cell membrane. Localization of Ras to the cell membrane is necessary for signal transduction (Willumsen, B M, et al., Science 310:583-586 (1984)).
Oncogenic forms of Ras are observed in a relatively large number of cancers including over 50 percent of colon cancers and over 90 percent of pancreatic cancers (Bos, J L, Cancer Research 49:4682-4689 (1989)). These observations suggest that intervention in the function of Ras mediated signal transduction may be useful in the treatment of cancer.
Previously, it has been shown that the C-terminal tetrapeptide of Ras is a xe2x80x9cCAAXxe2x80x9d motif (wherein C is cysteine, A is an aliphatic amino acid, and X is any amino acid). Tetrapeptides having this structure have been shown to be inhibitors of prenyl transferases (Reiss, et al., Cell 62:81-88 (1990)). Poor potency of these early farnesyl transferase inhibitors has prompted the search for new inhibitors with more favorable pharmacokinetic behavior (James, G L, et al., Science 260:1937-1942 (1993); Kohl, N E, et al., Proc. Nat""l Acad. Sci. USA 91:9141-9145 (1994); deSolms, SJ, et al., J. Med. Chem. 38:3967-3971 (1995); Nagasu, T, et al., Cancer Research 55:5310-5314 (1995); Lerner, E C, et al., J. Biol. Chem. 270:26802-26806 (1995); Lerner, E C, et al., J. Biol. Chem. 270:26770 (1995); and James, et al., Proc. Natl. Acad. Sci. USA 93:4454 (1996)).
Recently, it has been shown that a prenyl transferase inhibitor can block growth of Ras-dependent tumors in nude mice (Kohl, N. E., et al., Proc. Nat""l Acad. Sci. USA 91:9141-9145 (1994)). In addition, it has been shown that over 70 percent of a large sampling of tumor cell lines are inhibited by prenyl transferase inhibitors with selectivity over non-transformed epithelial cells (Sepp-Lorenzino, I., et al., Cancer Research, 55:5302-5309 (1995)).
In one aspect, this invention provides a compound of formula (I), 
or a pharmaceutically acceptable salt thereof,
wherein
xe2x80x94xe2x80x94xe2x80x94xe2x80x94xe2x80x94xe2x80x94xe2x80x94represents an optional bond;
m, n, p, and q are each independently 0 or 1;
T for each occurrence is independently selected from the group consisting of CR26R27, S, O, C(O), S(O)2 and NR28;
X is Nxe2x80x94Y, O or S where Y is selected from the group consisting of H, CR14R15R16, S(O)R17, S(O)2R18, C(O)R19, C(O)NR20R21, C(S)NR22R23, C(O)OR24, C(S)OR25, S(O)NR29R30 and S(O)2NR31R32;
Z is selected from the group consisting of H, cyano, halo, CR14R15R16, S(O)R17, S(O)2R18 and C(O)R19;
R1, R2, R3, R4, R5, R6, R11, R12, R13, R14, R15, R16, R26 and R27 are each independently selected from the group consisting of H, halo, hydroxy, thio and cyano, or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino and alkyl carbonyl amino;
or R1 and R2 when on adjacent positions, or R4 and R5, or R11 and R12, are taken together to form a bivalent radical selected from the group consisting of xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 and xe2x80x94CR33xe2x95x90CR34xe2x80x94CR35xe2x95x90CR36xe2x80x94; R7, R8 and R9 are each independently selected from the group consisting of H, halo, aryl, alkyl, substituted alkyl, alkyloxy, alkylthio, aryloxy, arylthio amino, mono- or di-alkylamino, hydroxycarbonyl, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)2-alkyl, cyanoarylalkyl, arylalkyl and substituted arylakyl;
R10 is selected from the group consisting of H, amino, azido, hydroxy, halo, alkyl, substituted alkyl, cyano, hydroxyalkyl, hydroxycarbonyl, aminoalkyl, mono- or di-alkylaminoalkyl, mono- or di-alkylamino, alkoxy, alkylcarbonylalkyl, cyanoalkyl, alkyloxycarbonylalkyl, carboxyalkyl, cycloalkyl, cycloalkylamino, cycloalkylhydroxy, imidazoyl, substituted imidazoyl, aminocarbonylalkyl, aryloxy, thio, alkylthio, OS(O2)R18, OC(O)R19, OC(O)NR20R21, OC(S)NR22R23, OS(O)NR29R30, OS(O)2NR31R32 and arylthio; and R17, R18, R19, R20, R21, R22, R23, R24, R25, R28, R29, R30, R31, R32 and R37 for each occurrence are each independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl and arylalkyl;
or R20 and R21, or R22 and R23, or R29 and R30, or R31 and R32 are taken together to form a bivalent radical selected from the group consisting of xe2x80x94(CH2)rxe2x80x94NR37xe2x80x94(CH2)sxe2x80x94, xe2x80x94(CH2)rxe2x80x94Oxe2x80x94(CH2)sxe2x80x94 and xe2x80x94(CR38R39)txe2x80x94, where r and s are each independently 1 to 3 and t is 2 to 6;
R33, R34, R35, R36, R38 and R39 are each independently selected from the group consisting of H, halo, cyano, alkyl, substituted alkyl, aryl, substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, hydroxy and thio.
A preferred group of compounds of the immediately foregoing compounds is where m, n, p and q are each 0.
A preferred group of compounds of the immediately foregoing compounds is where R1, R2, R3, R4, R5, R6, R11, R12 and R13 are each H, halo, alkyl, substituted alkyl, cyano or alkyloxy.
A preferred group of compounds of the immediately foregoing compounds is where R10 is OH, H, halo, azido, amino, mono- or di-alkylamino, OS(O2)R18, OC(O)NR20R21 or OS(O)2NR31R32.
A preferred group of compounds of the immediately foregoing compounds is where R7, R8 and R9 are each H, alkyl, substituted alkyl, amino or cyanoarylalkyl.
A preferred group of compounds of the immediately foregoing compounds is where X is Nxe2x80x94Y and Y is H, CR14R15R16, S(O)2R18, C(O)NR20R21 or S(O)2NR29R30.
A preferred group of compounds of the immediately foregoing compounds is where R1, R2, R3, R11, R12 and R13 are each halo or hydrogen.
A preferred group of compounds of the immediately foregoing compounds is where R1, R2, R3, R11, R12 and R13 are each chloro or hydrogen.
A preferred group of compounds of the immediately foregoing compounds is where R7, R8, and R9 are each (C1-C4)alkyl or hydrogen.
A preferred group of compounds of the immediately foregoing compounds is where R7, R8, and R9 are each methyl or hydrogen.
A preferred group of compounds of the immediately foregoing compounds is where R10 is OH, amino, OS(O2)R18, or OC(O)NR20R21.
A preferred group of compounds of the immediately foregoing compounds is where R4, R5 and R6 are each H.
A preferred group of compounds of the immediately foregoing compounds is where Z is hydrogen.
A preferred group of compounds of the immediately foregoing compounds is where Y is H, methyl, S(O)2R18, C(O)NR20R21 or S(O)2R29R30.
A preferred group of compounds of the immediately foregoing compounds is where said compounds are of the formula: 
wherein
R10 is OH and Y is H;
R10 is NH2 and Y is xe2x80x94S(O)2xe2x80x94CH3;
R10 is OH and Y is xe2x80x94S(O)2xe2x80x94CH3;
R10 is OH and Y is xe2x80x94C(O)xe2x80x94N(CH3)2;
R10 is NH2 and Y is xe2x80x94C(O)xe2x80x94N(CH3)2;
R10 is NH2 and Y is H;
R10 is OH and Y is 
R10 is NH2 and Y is 
R10 is OH and Y is xe2x80x94S(O)2-Phenyl;
R10 is NH2 and Y is xe2x80x94S((O)2-Phenyl;
R10 is OH and Y is xe2x80x94C(O)xe2x80x94N(CH2CH3)2;
R10 is NH2 and Y is xe2x80x94C(O)xe2x80x94N(CH2CH3)2;
R10 is OH and Y is xe2x80x94CH3; and
R10 is NH2 and Y is xe2x80x94CH3.
A preferred group of compounds of the immediately foregoing compounds is where said compounds are of the formula 
wherein
R10 is OH and Y is H;
R10 is NH2 and Y is xe2x80x94S(O)2xe2x80x94CH3;
R10 is OH and Y is xe2x80x94S(O)2xe2x80x94CH3;
R10 is NH2 and Y is xe2x80x94S(O)2xe2x80x94CH3; and
R10 is OH and Y is xe2x80x94C(O)xe2x80x94N(CH3)2.
A preferred group of compounds of the immediately foregoing compounds is where said compounds are of the formula 
wherein
R10 is OH and Y is H; and
R10 is OH and xe2x80x94S(O)2xe2x80x94CH3.
In another aspect, this invention provides a compound of formula (II), 
or a pharmaceutically acceptable salt thereof,
wherein
xe2x80x94xe2x80x94xe2x80x94xe2x80x94xe2x80x94xe2x80x94xe2x80x94 represents an optional bond, provided that only one of the optional bonds is present in a compound of formula (I);
m, n, p, and q are each independently 0, 1 or 2;
T1, T2, T3 and T4 for each occurrence are each independently selected from the group consisting of CR26R27, S, O, C(O), S(O)2 and NR28;
X is Nxe2x80x94Y, O or S where Y is selected from the group consisting of H, CR14R15R16, S(O)R17, S(O)2R18, C(O)R19, C(O)NR20R21, C(S)NR22R23, C(O)OR24, C(S)OR25, S(O)NR29R30 and S(O)2NR31R32;
Z is selected from the group consisting of H, hydroxy, alkoxy, aryloxy, cyano, halo, C14R15R16, S(O)R17, S(O)2R18, C(O)R19, C(O)NR20R21, C(O)OR24, C(S)NR22R23, C(S)OR25, S(O)NR29R30 and S(O)2NR31R32, provided that when the optional bond connected to Z is present then Z is oxygen or sulfur;
R1, R2, R3, R4, R5, R6, R11, R12, R13, R14, R15, R16, R26 and R27 for each each independently selected from the group consisting of H, halo, hydroxy, thio and cyano, or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino and alkyl carbonyl amino;
or each pair of R1 and R2, R4 and R5, and R11 and R12 when on adjacent positions, is independently taken together to form a bivalent radical selected from the group consisting of xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 and xe2x80x94CR33xe2x95x90CR34xe2x80x94CR35xe2x95x90CR36xe2x80x94;
R7, R8 and R9 are each independently H, halo, amino, cyano, hydroxycarbonyl, or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkyloxy, alkylthio, aryloxy, arylthio, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)2-alkyl, cyanoarylalkyl and arylalkyl, provided that when R7, R8 or R9 is bound to one of the nitrogen atoms of the imidazolyl ring, R7, R8 or R9 is H or an optionally substituted moiety selected from the group consisting of aryl, alkyl, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)2-alkyl, cyanoarylalkyl and arylalkyl;
R10 is selected from the group consisting of H, amino, azido, hydroxy, halo, alkyl, substituted alkyl, cyano, hydroxycarbonyl, mono- or di-alkylamino, alkyloxy, cycloalkyl, cycloalkylamino, cycloalkyloxy, imidazolyl, substituted imidazolyl, aryloxy, thio, alkylthio, arylthio, OS(O)2R18, OC(O)R19, OC(O)NR20R21, OC(S)NR22R23, OS(O)NR29R30 and OS(O)2NR31R32;
R17 and R18, for each occurrence are each independently H, OH or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;
R19, R20, R21, R22, R23, R24, R25, R28, R29, R30, R31 and R32 for each occurrence a independently H or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;
or each pair of R20 and R21, R22 and R23, R29 and R30, and R31 and R32 is independently taken together to form a bivalent radical selected from the group consisting of xe2x80x94(CH2)rxe2x80x94NR40xe2x80x94(CH2)s, xe2x80x94(CH2)rxe2x80x94Oxe2x80x94(CH2)sxe2x80x94, xe2x80x94(CR38R39)txe2x80x94 and xe2x80x94(CH2)rxe2x80x94NR40xe2x80x94(C(O))uxe2x80x94, where r and s are each independently 1 to 3, t is 2 to 6 and u is 1 or 2;
R33, R34, R35, R36, R38 and R39 for each occurrence are each independently selected from the group consisting of H, amino, halo, cyano, alkyl, substituted alkyl, aryl, substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio, mono- or di-alkylamino, arylamino, hydroxy, heterocyclyl and thio;
and R40 is H, S(O)2R18, C(O)R19, C(O)NR20R21, C(S)NR22R23, C(O)OR24, C(S)OR25, S(O)2NR31R32 or an optionally substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl.
A preferred group of compounds of the immediately foregoing compounds is where m, n, p and q are each 0.
A preferred group of compounds of the immediately foregoing compounds is where R1, R2, R3, R4, R5, R6, R11, R12 and R13 are each H, halo, alkyl, substituted alkyl, cyano or alkyloxy.
A preferred group of compounds of the immediately foregoing compounds is where R10 is OH, H, halo, azido, amino, mono- or di-alkylamino, OS(O)2R18, OC(O)NR20R21 or OS(O)2NR31R32.
A preferred group of compounds of the immediately foregoing compounds is where R7, R8 and R9 are each H, alkyl, substituted alkyl or cyanoarylalkyl.
A preferred group of compounds of the immediately foregoing compounds is where X is Nxe2x80x94Y and Y is H, CR14R15R16, S(O)2R18, C(O)R19, C(O)NR20R21, C(O)OR24 or S(O)2NR31R32.
A preferred group of compounds of the immediately foregoing compounds is where R1, R2, R3, R11, R12 and R13 are each halo or H.
A preferred group of compounds of the immediately foregoing compounds is where R1, R2, R3, R11, R12 and R13 are each chloro or H.
A preferred group of compounds of the immediately foregoing compounds is where R7, R8, and R9 are each (C1-C4)alkyl or H.
A preferred group of compounds of the immediately foregoing compounds is where R7, R8, and R9 are each methyl or H.
A preferred group of compounds of the immediately foregoing compounds is where R10 is OH, amino, OS(O)2R18, OC(O)NR20R21 or OS(O)2NR31R32.
A preferred group of compounds of the immediately foregoing compounds is where R4, R5 and R6 are each H.
A preferred group of compounds of the immediately foregoing compounds is where Z is hydrogen, halo or C(O)NR20R21.
A preferred group of compounds of the immediately foregoing compounds is where Y is H, methyl, S(O)2R18, C(O)R19, C(O)NR20R21, C(O)OR24 or S(O)2NR31R32.
A preferred group of compounds of the immediately foregoing compounds is where said compounds are of the formula: 
wherein
Z is H, R10 is OH and Y is H;
Z is H, R10 is NH2 and Y is xe2x80x94S(O)2xe2x80x94CH3;
Z is H, R10 is OH and Y is xe2x80x94S(O)2xe2x80x94CH3;
Z is H, R10 is OH and Y is xe2x80x94C(O)xe2x80x94N(CH3)2;
Z is H, R10 is NH2 and Y is xe2x80x94C(O)xe2x80x94N(CH3)2;
Z is H, R10 is NH2 and Y is H;
Z is H, R10 is OH and Y is 
Z is H, R10 is NH2 and Y is 
Z is H, R10 is OH and Y is xe2x80x94S(O)2-Phenyl;
Z is H, R10 is NH2 and Y is xe2x80x94S(O)2-Phenyl;
Z is H, R10 is OH and Y is xe2x80x94C(O)xe2x80x94N(CH2CH3)2;
Z is H, R10 is NH2 and Y is xe2x80x94C(O)xe2x80x94N(CH2CH3)2;
Z is H, R10 is OH and Y is xe2x80x94CH3;
Z is H, R10 is NH2 and Y is xe2x80x94CH3; 
Z is H, R10 is OH and Y is
Z is H, R10 is NH2 and Y is 
Z is H, R10 is OH and Y is 
Z is H, R10 is NH2 and Y is 
Z is H, R10 is OH and Y is 
Z is H, R10 is NH2 and Y is 
Z is H, R10 is OH and Y is xe2x80x94C(O)xe2x80x94CH3;
Z is H, R10 is NH2 and Y is xe2x80x94C(O)xe2x80x94CH3;
Z is H, R10 is OH and Y is xe2x80x94S(O)2xe2x80x94CF3;
Z is H, R10 is NH2 and Y is xe2x80x94S(O)2xe2x80x94CH2xe2x80x94CF3;
Z is H, R10 is OH and Y is xe2x80x94S(O)2xe2x80x94CH2xe2x80x94CF3;
Z is H, R10 is NH2 and Y is xe2x80x94S(O)2xe2x80x94CH2xe2x80x94CF3;
Z is H, R10 is OH and Y is 
Z is H, R10 is NH2 and Y is 
Z is H, R10 is OH and Y is 
Z is H, R10 is NH2 and Y is 
Z is H, R10 is OH and Y is 
Z is H, R10 is NH2 and Y is 
Z is H, R10 is OH and Y is 
Z is H, R10 is NH2 and Y is 
Z is H, R10 is OH and Y is xe2x80x94C(O)xe2x80x94NH2;
Z is H, R10 is NH2 and Y is xe2x80x94C(O)xe2x80x94NH2;
Z is H, R10 is OH and Y is 
Z is H, R10 is NH2and Y is 
Z is Cl, R10 is NH2 and Y is 
Z is Cl, R10 is NH2 and Y is xe2x80x94S(O)2xe2x80x94CH3;
Z is H, R10 is OH and Y is 
Z is H, R10 is NH2 and Y is 
Z is H, R10 is OH and Y is 
Z is H, R10 is NH2and Y is 
A preferred group of compounds of the immediately foregoing compounds is where said compounds are of the formula: 
wherein
Z is H, R10 is OH and Y is H;
Z is H, R10 is NH2 and Y is xe2x80x94S(O)2xe2x80x94CH3;
Z is H, R10 is OH and Y is xe2x80x94S(O)2xe2x80x94CH3;
Z is H, R10 is OH and Y is xe2x80x94C(O)xe2x80x94N(CH3)2;
Z is H, R10 is OH and Y is xe2x80x94C(O)xe2x80x94CH3; and
Z is H, R10 is NH2 and Y is xe2x80x94C(O)xe2x80x94CH3.
In another aspect, this invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or (II), as defined hereinabove, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
In yet another aspect, this invention provides a method of treating a tumor, fibrosis or restenosis in a subject in need thereof, which comprises administering to said subject an effective amount of a compound of formula (I) or (II), as defined hereinabove, or a pharmaceutically acceptable salt thereof.
In still another aspect, this invention provides a method of inhibiting prenyl transferase in a subject in need thereof, which comprises administering to said subject an effective amount of a compound of formula (I) or (II), as defined hereinabove, or a pharmaceutically acceptable salt thereof.
In yet another aspect, the present invention is directed to a process for synthesizing a compound of formula 3, according to the scheme below, which comprises reacting a compound of formula 1, according to the scheme below, with an arylalkylmagnesium chloride of formula 2, according to the scheme below, in which case X3 is Clxe2x80x94Mg and p=1-2, or an aryllithium of formula 2, in which case X3 is Li and p=0, in an inert organic solvent, until the reaction is substantially complete, 
wherein P is a protecting group and the other substituents are as defined for the compound of formula (II) hereinabove.
In still another aspect, the present invention is directed to a process for synthesizing a compound of formula 2, according to the scheme below, which comprises reacting a compound of formula 1, according to the scheme below, with a chlorinating reagent until the reaction is substantially complete, 
wherein the substituents are as defined for the compound of formula II hereinabove.
In an even further aspect, the present invention is directed to a process for synthesizing a compound of formula 3, according to the scheme below, which comprises reacting a compound of formula 2 with anhydrous liquid ammonia or an inert organic solvent saturated with anhydrous ammonia when n, p and q are each 0, or ammonium hydroxide when n, p and q are each not 0, until the reaction is substantially complete 
wherein the substituents are as defined for the compound of formula (II) hereinabove.
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.
In the portion of the compound of formula (I) or (II), where the two optional bonds are shown, only one of the optional bonds may be present in a compound. When the optional bond directly attached to the variable Z is present then Z is an oxygen or sulfur.
The term xe2x80x9calkylxe2x80x9d refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms.
The term xe2x80x9csubstituted alkylxe2x80x9d refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substitituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido, e.g. SO2NH2, substituted sulfonamido, nitro, cyano, carboxy, carbamyl, e.g. CONH2, substituted carbamyl e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected form alkyl, aryl or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocycles, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above where the substituent is further substituted it will be with alkyl, alkoxy, aryl or aralkyl.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to fluorine, chlorine, bromine and iodine.
The term xe2x80x9carylxe2x80x9d refers to monocyclic or bicyclic aromatic group having 6 to 12 carbon atoms in the ring portion such as phenyl, naphthyl, biphenyl and diphenyl, each of which may be substituted.
The term xe2x80x9carylalkylxe2x80x9d refers to an aryl group bonded directly through an alkyl group, such as benzyl.
The term xe2x80x9csubstituted arylxe2x80x9d refers to an aryl group substituted by, for example, one to five substituents such as alkyl; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, arylalkylamino, arylalkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkylsulfonyl, sulfonamido, aryloxy and the like. The substituent may be further substituted by hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl, or arylalkyl.
The term xe2x80x9calkenylxe2x80x9d refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four double bonds.
The term xe2x80x9csubstituted alkenylxe2x80x9d refers to an alkenyl group substituted by, for example, one to three substituents, such as, aryl, substituted aryl, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl pyridyl, pyrimidyl and the like.
The term xe2x80x9calkynylxe2x80x9d refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four triple bonds.
The term xe2x80x9csubstituted alkynylxe2x80x9d refers to an alkynyl group substituted by, for example, a substituent, such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclo, e.g. imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d refers to an optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl. Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The terms xe2x80x9cheterocyclexe2x80x9d, heterocyclic and xe2x80x9cheterocyclylxe2x80x9d refer to an optionally substituted, fully saturated or unsaturated, aromatic or non-aromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, 4 or 5 heteroatoms selected from nitrogen, oxygen and sulfur, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, tetrazolyl and triazolyl, and the like.
Exemplary bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl) or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazoliny (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxaxolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl, and the like.
Exemplary substituents include one or more alkyl groups as described above or one or more groups described above as alkyl substituents. Also included are smaller heterocycles, such as, epoxides and aziridines.
The term xe2x80x9cheteroatomsxe2x80x9d shall include oxygen, sulfur and nitrogen.
A compound of formula (I) or (II) may form pharmaceutically acceptable salts which are also within the scope of this invention. Pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolating or purifying the compounds of this invention.
A compound of formula (I) or (II) may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like. Such salts may be obtained, for example, by exchanging the carboxylic acid protons, if they contain a carboxylic acid, with the desired ion in a medium in which the salt precipitates or in an aqueous medium followed by evaporation. Other salts can be formed as known to those skilled in the art.
A compound of formula (I) or (II) may form salts with a variety of organic and inorganic acids. Such salts include those formed with hydrogen chloride, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and various others (e.g., nitrates, phosphates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like). Such salts may be formed by reacting a compound of formula (I) or (II) in an equivalent amount of the acid in a medium in which the salt precipitates or in an aqueous medium followed by evaporation.
As is well known to those skilled in the art, the known and potential uses of prenyl transferase inhibitors are varied and multitudinous, such as for treating restenosis or a tissue proliferative disease. Examples of tissue proliferative disease include both those associated with benign cell proliferation such as fibrosis, benign prostatic hyperplasia, atherosclerosis and restenosis; and those associated with malignant cell proliferation such as cancer (e.g., ras mutant tumors). Examples of such tumors include breast, colon, pancreas, prostate, lung, ovarian, epidermal and hematopoietic cancers (Sepp-Lorenzino, I, et al., Cancer Research, 55:5302, 1995). Other diseases and conditions that prenyl transferase inhibitors can be used for is in the treatment of neoplasm, fungal infection, arteriosclerosis, retina disease, hepatitis, renal disease, myeloid leukemia, viral infection, nervous system tumor and viral infection.
Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of Formula I in association with a pharmaceutically acceptable carrier.
The compounds of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and cornoil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as coca butter or a suppository wax.
Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
Further, a compound of this invention can be administered in a sustained release composition such as those described in the following patents. U.S. Pat. No. 5,672,659 teaches sustained release compositions comprising a bioactive agent and a polyester. U.S. Pat. No. 5,595,760 teaches sustained release compositions comprising a bioactive agent in a gelable form. U.S. application Ser. No. 08/929,363 filed Sep. 9, 1997, teaches polymeric sustained release compositions comprising a bioactive agent and chitosan. U.S. application Ser. No. 08/740,778 filed Nov. 1, 1996, teaches sustained release compositions comprising a bioactive agent and cyclodextrin. U.S. application Ser. No. 09/015,394 filed Jan. 29, 1998, teaches absorbable sustained release compositions of a bioactive agent. The teachings of the foregoing patents and applications are incorporated herein by reference.
The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. Generally, dosage levels of between 0.0001 to 100 mg/kg of body weight daily are administered to humans and other animals, e.g., mammals, to obtain effective release of growth hormone.
A preferred dosage range is 0.01 to 100.0 mg/kg of body weight daily which can be administered as a single dose or divided into multiple doses.
A compound of formula (I) or (II) can be tested for activity as an inhibitor of prenyl transferase according to the following in vitro assay.
Farnesyl transferase activity is assayed by [3H] farnesylation of recombinant human H-Ras protein wild type, using microplate and filtration method. Incubation mixture contains, in a total volume of 25 xcexcl: 50 mM Tris HCl (pH 7.5), 5 mM dithiothreitol, 20 xcexcM ZnCl2, 40 mM MgCl2, 0.6 xcexcM [3H] farnesyl pyrophosphate (22.3 Ci/mmol), 4 xcexcM H-Ras and 10 xcexcg of farnesyl transferase from human brain cytosol. Test compounds are added in adequate solvent and incubations start by addition of farnesyl transferase. After approximately 60 minutes at approximately 37xc2x0 C., the reaction is stopped by addition of 100 xcexcl of 10% HCl in ethanol and allowed to incubate approximately 15 minutes at approximately 37xc2x0 C., then 150 xcexcl of absolute ethanol are added and incubation mixture is filtered on Unifilter GF/B microplates and washed 6 times with ethanol. After addition of 50 xcexcl of Microscint 0, plates were counted on a Packard Top Count scintillation counter. Geranylgeranyl transferase activity is assayed by the same method, but using 4 xcexcM human recombinant H-Ras CVLL type, 0.6 xcexcM [3H] geranylgeranyl-pyrophosphate (19.3 Ci/mmol) and 100 xcexcg of geranylgeranyltransferase from human brain.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Also, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference.
The compounds of the present invention can be made according to the following schemes and associated descriptions and by methods well-known to those of ordinary skill in the art. The starting materials and reagents are either commercially available or can be synthesized according to published procedures well-known to those of ordinary skill in the art. The substituents have the same definitions as for the compound of formula (II), shown hereinabove. 
This reaction is accomplished by the reaction of an aldehyde or ketone of formula 1 with a phenylhydrazine of formula 2 in a mixed acid/organic solvent or an acid solvent, such as acetic acid at an elevated temperature, preferably at reflux temperatures. 
Step 1
In Scheme 2, starting material 1 has a protecting group, P1, such as a phenylsulfonyl or methylsulfonyl group, at position 1 of the indole ring. An indole of formula 1 is treated in an organic solvent, such as tetrahydrofuran, with active zinc at about room temperature to give 3-indolylzinc iodide 2.
Step 2
Thereafter product 2 is coupled with an iodo- or bromo-aromatic system 3 (X1=l or Br), such as iodobenzene in the presence of a catalyst, such as tetrakis(triphenylphosphine)palladium in an organic solvent at about room temperature.
Step 3
Thereafter product 3 is hydrolyzed by using an appropriate base, such as KOH or NaOH in a suitable solvent, such as methanol at from about 0xc2x0 C. to about 100xc2x0 C. This step may also be accomplished by treating with tetraalkylammonium fluoride, such as tetrabutylammonium fluoride in a suitable organic solvent, such as tetrahydrofuran, at an elevated temperature, preferably reflux temperatures. 
Step 1
In Scheme 3, compound 1 is reduced by using an appropriate reducing agent, such as borane in an organic solvent containing a suitable acid, such as tetrahydrofuran containing trifluoroacetic acid at from about 0xc2x0 C. to about room temperature.
Step 2
Thereafter product 2 is protected by reacting with an appropriate agent, such as methanesuffonyl chloride, xcfx81-toluenesulfonyl chloride or phenylsulfonyl chloride in the presence of a base, such as triethylamine or N,N-diisopropylethylamine in an inert organic solvent, such as dichloromethane or N,N-dimethylformamide at from about xe2x88x9278xc2x0 C. to about room temperature.
Step 3
Thereafter product 3 is coupled with the chloride acid 4 in the presence of an acid or Lewis acid, such as aluminum chloride, in a solvent, such as carbon disulfide or dichloromethane at from about xe2x88x9278xc2x0 C. to an elevated temperature such as 100xc2x0 C. 
In Scheme 4, compound 1 is oxidized by reacting it with an oxidizing agent, for example, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or manganese (III) acetate dihydrate in an organic solvent, such as dioxane or acetic acid from about room temperature to about 150xc2x0 C. 
In Scheme 5, compound 1 which has an iodo- or bromo-substituent at position 2 (X2=I or Br) is reacted with an alkyne 2 in the presence of a suitable catalyst, such as palladium(II) acetate, an appropriate base such as potassium carbonate and other agents which are necessary for the reaction, such as triphenylphosphine/lithium chloride in an organic solvent, such as N,N-dimethylformamide at from about room temperature to about 150xc2x0 C. 
Step 1
In scheme 6, compound 1 is treated with nitrous acid in a solvent, such as water or sulfuric acid at from about 0xc2x0 C. to 50xc2x0 C.
Step 2
Thereafter product 2 is reacted with compound 3 in the presence of a suitable base, such as potassium hydroxide in a solvent such as water at about 0xc2x0 C. The mixture is treated with an acid, such as ethanolic hydrogen chloride at from about 50xc2x0 C. to about 80xc2x0 C. 
Step 1
In Scheme 7, compound 1 is hydrolyzed by reacting with a base, such as potassium hydroxide or sodium hydroxide in a solvent mixture, such as water/ethanol or a solvent, such as ethanol or water at an elevated temperature, preferably at reflux temperatures.
Step 2
Thereafter product 2 is reacted with a primary or secondary amine in the presence of a coupling agent such as 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and a base, such as dilsopropylethylamine in an organic solvent, such as N,N-dimethylformamide at from about 0xc2x0 C. to about room temperature. 
In Scheme 8, the reaction is accomplished by reacting 1 with an appropriate decarboxylating agent, such as quinoline/copper at an elevated temperature, preferably at reflux temperatures to obtain a compound of formula 2. 
Step 1
In Scheme 9, compound 1 is reduced by reacting with a suitable reducing agent, such as sodium borohydride in a suitable organic solvent, such as ether or tetrahydrofuran, yielding intermediate 2.
Step 2
Thereafter product 2 is reacted with an appropriate reagent, such as thionyl chloride or methanesulfonyl chloride to convert the hydroxy group into an active leaving group, such as chloro- or methylsulfonate group (L1=Cl or CH3S(O)2Oxe2x80x94).
Step 3
Thereafter product 3 is reacted with an imidazole of formula 4 in the presence of a suitable base, such as potassium carbonate in an organic solvent, such as acetonitrile at an elevated temperature, preferably at reflux temperatures. If the optional protecting group P is not stable under the reaction condition and hydrolyzed, another additional step may be needed to introduce the Y group at the nitrogen in the indole ring. If this additional step is required, the intermediate is treated with Yxe2x80x94L, in which L is an active leaving group, for example Yxe2x80x94Cl, e.g., methanesulfonyl chloride or dimethylcarbamoyl chloride, in an inert organic solvent at from about xe2x88x9278xc2x0 C. to about room temperature. 
In Scheme 10, compound 1 is reacted with an imidazole of formula 2, in which R7 is an optional protective group, such as a dimethylamino sulfonyl group, which can be removed after the addition. The reaction takes place in the presence of a suitable base, such as butyl lithium. If R8 is hydrogen at position 2 of the imidazole then it needs to be temporarily protected with a protecting group, such as triethylsilane by reacting it with an appropriate reagent, such as chlorotriethylsilane. If the optional protective group P, such as a methylsulfonyl group is not stable under the reaction condition and cleaved off, another reagent which can introduce a Y group at the nitrogen of the indole ring, for example Yxe2x80x94Cl, e.g., methanesulfonyl chloride or dimethylcarbamoyl chloride, may be added into the reaction mixture to obtain the desired compound 3. The chlorotriethylsilyl group is hydrolyzed during the work-up procedure. 
In Scheme 11, compound 1 is reacted with an arylalkylmagnesium chloride (X3=Clxe2x80x94Mg, p=1-2) or an aryllithium (X3=Li, p=0) shown as compound 2, in an inert organic solvent, such as tetrahydrofuran. If the optional protective group P, is not stable under the reaction condition and cleaved off, another reagent which can introduce a Y group at the nitrogen of the indole ring, for example Yxe2x80x94Cl, e.g., methanesulfonyl chloride or dimethylcarbamoyl chloride, may be added into the reaction mixture to obtain the desired compound 3. 
Step 1
In Scheme 12, the first reaction is accomplished by the reaction of an aldehyde or ketone of formula 1 with a phenylhydrazine or its derivative of formula 2 in a mixed acid/organic solvent or an acid solvent, such as acetic acid at an elevated temperature, preferably at reflex temperature.
Step 2
Thereafter product 3 is reacted with Yxe2x80x94L, in which L is an active leaving group, such as a chloride group, in the presence of a suitable base, such as triethylamine or diisopropylethylamine in an inert organic solvent, such as dichloromethane or N,N-dimethylformamide at from about xe2x88x9278xc2x0 C. to about room temperature.
Step 3
Thereafter product 4 is converted into alkyl- (n=1 or 2) or arylmagnesium (n=0, M=MgX3, in which X3=halide, e.g., Cl or Br) halide or alkyl-(n=1 or 2) or aryl-(n=0, M=Li) lithium by reacting with metallic magnesium, lithium metal or alkyllithium, such as butyllithium in an inert organic solvent, such as ether or tetrahydrofuran at about xe2x88x9212xc2x0 C. to about room temperature.
Step 4
Thereafter product 5 is reacted with ketone 6 in an inert organic solvent, such as ether or tetrahydrofuran at from about xe2x88x9212xc2x0 C. to about room temperature. 
Step 1
In Scheme 13, starting material 1 is reduced by reacting with a reducing agent, such as borane in an organic solvent, such as tetrahydrofuran containing an acid, such as trifluoroacetic acid at from about 0xc2x0 C. to about room temperature.
Step 2
Thereafter product 2 is reacted with Yxe2x80x94L, in which L is an active leaving group, such as a chloro group, in the presence of a suitable base, such as triethylamine or diisopropylethylamine in an organic solvent, such as dichloromethane or N,N,-dimethylformamide at from about xe2x88x9278xc2x0 C. to about room temperature, yielding compound 3.
Step 3
Thereafter product 3 is converted into alkyl-(n=1 or 2) or arylmagnesium (n=0, M=MgX5, in which X5=halide, e.g., Cl or Br) halide or alkyl-(n=1 or 2) or aryl-(n=0) lithium (M=Li) by reacting with metallic magnesium, lithium metal or alkyllithium, such as butyllithium in an inert organic solvent, such as ether or tetrahydrofuran at about xe2x88x9212xc2x0 C. to about room temperature.
Step 4
Thereafter product 4 is reacted with ketone 5 in an inert organic solvent, such as ether or tetrahydrofuran at from about xe2x88x9212xc2x0 C. to about room temperature. 
In Scheme 14, compound 1 can be converted to compound 2 by reacting with a suitable group of reagents, such as methyl sulfoxide/concentrated HCl or potassium persulfate/sodium acetate in a suitable solvent such as water or an alcohol. 
In Scheme 15, compound 1 can be convened to compound 3 by reacting with compound 2 in the presence of suitable base. 
In Scheme 16, compound 1 can be converted to compound 3 by reacting it with compound 2 under suitable conditions. 
Step 1
In Scheme 17, compound 1 is converted to compound 2, in which P4xe2x80x94Oxe2x80x94 is an active leaving group, such as methylsulfonate, p-toluenesulfonate or trifluoromethanesulfonate by reacting it with a suitable reagent, such as methanesulfonyl chloride, xcfx81-toluenesulfonyl chloride or trifluoromethanesulfonic anhydride in an inert organic solvent, such as dichloromethane.
Step 2
Thereafter product 2 is reacted with sodium azide to yield compound 3 in an organic solvent, such as N,N-dimethylformamide at from about room temperature to an elevated temperature, such as about 60xc2x0 C.
Step 3
Thereafter product 3 is reduced to compound 4 by reacting it with an appropriate reducing agent, such as triphenylphosphine with water in a suitable solvent such as pyridine. 
Step 1
In Scheme 18, compound 1 can be converted to compound 2 which has an active leaving group, such as a chloro group, by reacting with an appropriate reagent, such as thionyl chloride at from about room temperature to an elevated temperature, preferably at about 38xc2x0 C.
Step 2
Thereafter product 2 is reacted with an appropriate agent, such as liquid ammonia at from low temperature, such as xe2x88x9278xc2x0 C., to an elevated temperature.